title: Biochemical changes accompanying apoptotic cell death in retinoblastoma cancer cells treated with lipogenic enzyme inhibitors.
abstract: Retinoblastoma (RB) is a malignant intra-ocular neoplasm that affects children (usually below the age of 5years). In addition to conventional chemotherapy, novel therapeutic strategies that target metabolic pathways such as glycolysis and lipid metabolism are emerging. Fatty acid synthase (FASN), a lipogenic multi-enzyme complex, is over-expressed in retinoblastoma cancer. The present study evaluated the biochemical basis of FASN inhibition induced apoptosis in cultured Y79 RB cells. FASN inhibitors (cerulenin, triclosan and orlistat) significantly inhibited FASN enzyme activity (P<0.05) in Y79 RB cells. This was accompanied by a decrease in palmitate synthesis (end-product depletion), and increased malonyl CoA levels (substrate accumulation). Differential lipid profile was biochemically estimated in neoplastic (Y79 RB) and non-neoplastic (3T3) cells subjected to FASN inhibition. The relative proportion of phosphatidyl choline to neutral lipids (triglyceride+total cholesterol) in Y79 RB cancer cells was found to be higher than the non-neoplastic cells, indicative of altered lipid distribution and utilization in tumor cells. FASN inhibitor treated Y79 RB and fibroblast cells showed decrease in the cellular lipids (triglyceride, cholesterol and phosphatidyl choline) levels. Apoptotic DNA damage induced by FASN inhibitors was accompanied by enhanced lipid peroxidation.
authors.affiliation: Dept. of Ocular Pathology, Vision Research Foundation, Sankara Nethralaya, Chennai, India.
authors.forename: Suryanarayanan
authors.initials: S
authors.lastname: Vandhana
authors.forename: Karunakaran
authors.initials: K
authors.lastname: Coral
authors.forename: Udayakumar
authors.initials: U
authors.lastname: Jayanthi
authors.forename: Perinkulam Ravi
authors.initials: PR
authors.lastname: Deepa
authors.forename: Subramanian
authors.initials: S
authors.lastname: Krishnakumar
mesh_terms: D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008055:Lipids / Q000032:analysis; D008315:Malondialdehyde / Q000378:metabolism; D008316:Malonyl Coenzyme A / Q000378:metabolism; D051379:Mice; D012175:Retinoblastoma / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*
chemical_list: D004791:Enzyme Inhibitors; D005230:Fatty Acids, Nonesterified; D008055:Lipids; D008315:Malondialdehyde; D008316:Malonyl Coenzyme A; D064429:Fatty Acid Synthases
keywords: Apoptosis; Fatty acid synthase; Malonyl CoA; Oxidative stress; Phospholipid; Retinoblastoma